(a) Field of the Invention
The present invention provides a controlled release pharmaceutical composition comprising a melt-extruded pellet including a water-insoluble ammonium methacrylate copolymer, a polyvinyl acetate and an active ingredient; and a polymer coating layer including a water-insoluble ammonium methacrylate copolymer formed on the surface of the pellet, and an oral formulation including the pharmaceutical composition.
(b) Description of the Related Art
A controlled release pharmaceutical formulation is advantageous in maintaining the drug efficacy time and reducing the side-effect, by controlling the release of active ingredient to stay the drug blood level at a target region for a long time. In addition, the controlled release pharmaceutical formulation is in the limelight, because it improves the patient's convenience by reducing the number of administration, and because it increases the treatment efficiency by maintaining the suitable blood level and the safety by reducing the side-effect. The controlled release formulation needs for a patient who needs frequent administration, for example, 2 to 4 times a day and has low medication compliance.
In the schizophrenia, the psychotic state mixed with at least one of emotional, behavioral, and mental weakness is lasted continuously or reoccurred and thus needs long-term treatment. Because a patient denies the frequent administration, the controlled release formulation has been developed for oral administration once daily or delayed action injections for a week or a month.
Paliperidone is atypical schizophrenia therapeutic called as 9-hydroxy-risperidone. Janssen has launched paliperidone as an slow-release drug formulation of Osmotic Release Oral delivery System which releases the paliperidone at zero order kinetics by administering once in a day (INVEGA™ extended-release tablet) and paliperidone palmitate as an injections administered one in a month (INVEGA™ Sustenna). Paliperidone is one of active metabolite of risperidone and has an additional hydroxyl group compared to risperidone. Paliperidone has been used for treating acute and chronic schizophrenia. Paliperidone obviates the hepatic drug metabolism, and thus is not seriously affected by dyshepatia, injury of liver, metabolic enzyme, the patient's condition and the like. Paliperidone is poorly soluble in water, and thus is well dissolved in methylene chloride, methanol and 0.1N hydrochloric acid.
Recently, the hot melt extrusion method which was used in the plastic manufacturing process has been introduced to the pharmaceutical industry to increase the bioavailability and to provide the controlled release drug formulation.
U.S. Pat. No. 6,488,963 discloses the preparation of controlled release formulation by extruding an active ingredient and Poly(ethylene oxide) having a high molecular weight of 1,000,000 to 10,000,000 according to the hot melt extrusion method. Although the composition can provide the delayed release formulation with 12 hours or shorter of drug release time, it has difficulty in preparing the delayed release formulation with the drug release time longer than 12 hours.
KR10-1189038 discloses a controlled release formulation including multi-particles produced by the hot melt extrusion method, which includes an active ingredient and a rubber-shape matrix of neutral poly(ethylacrylatemethylmethacrylate) copolymer. All available poly(ethylacrylatemethylmethacrylate) copolymer are sold in an aqueous dispersion and thus needs an additional step such as a wet-granulation disadvantageously.
WO1996/14058 discloses a melt-extruded blend including a drug and one or more hydrophobic materials selected from the group consisting of alkylcellulose, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil and a mixture thereof.
However, the publications related with the melt-extruded formulation cannot provide the controlled release formulations for various drugs and with a long release time over 12 hours, pH-independent drug release or drug release at zero order kinetics.
Therefore, the controlled release formulation which can control the side-effect of rapid drug release, extend the drug release time, and adjust the drug release pattern to the desired pattern and to close to zero order kinetics without being affected by pH condition, is still needed.